Cyano-substituted imidazo[1,2-A]pyridinecarboxamides and their use

Abstract

The present application relates to novel substituted imidazo[1,2-a]pyridine-3-carboxamides, to processes for preparation thereof, to the use thereof, alone or in combinations, for the treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for the treatment and/or prophylaxis of diseases, especially for the treatment and/or prophylaxis of cardiovascular disorders.

The invention claimed is: 
     
       1. Compound of the formula (I) 
       
         
           
           
               
               
           
         
         in which 
         A represents CH 2 , CD 2  or CH(CH 3 ), 
         R 1  represents (C 4 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, pyridyl or phenyl,
 where (C 4 -C 6 )-alkyl may be up to hexasubstituted by fluorine, 
 where (C 3 -C 7 )-cycloalkyl may be substituted by 1 to 4 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl and (C 1 -C 4 )-alkyl, 
 and 
 where phenyl may be substituted by 1 to 4 substituents independently of one another selected from the group consisting of halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, (C 1 -C 4 )-alkyl, (C 3 -C 5 )-cycloalkyl, (C 1 -C 4 )-alkoxy, difluoromethoxy and trifluoromethoxy, or may be substituted on two adjacent carbon atoms in the phenyl by a difluoromethylenedioxy bridge, 
 where pyridyl may be substituted by 1 to 4 substituents independently of one another selected from the group consisting of fluorine, monofluoromethyl, difluoromethyl, trifluoromethyl and (C 1 -C 4 )-alkyl, 
 
         R 2  represents hydrogen, (C 1 -C 4 )-alkyl, cyclopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl, 
         R 3  represents a group of the formula 
       
       
         
           
           
               
               
           
         
         
           where 
           * represents the point of attachment to the carbonyl group, 
           L 1  represents a bond or (C 1 -C 4 )-alkanediyl,
 in which (C 1 -C 4 )-alkanediyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl, hydroxy and (C 1 -C 4 )-alkoxy, 
 
           L 2  represents a bond or (C 1 -C 4 )-alkanediyl,
 in which (C 1 -C 4 )-alkanediyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl, hydroxy and (C 1 -C 4 )-alkoxy, 
 
           R 7  represents hydrogen, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl, —(C═O)—NR 9 R 10 , (C 1 -C 4 )-alkoxycarbonyl, amino, hydroxy, 5- or 6-membered heteroaryl or phenyl,
 in which (C 1 -C 6 )-alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxy, (C 3 -C 7 )-cycloalkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkoxycarbonyl, amino, phenyl, phenoxy and benzyloxy,
 in which phenyl, phenoxy and benzyloxy for their part may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen and cyano, 
 
 in which (C 3 -C 7 )-cycloalkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkoxy, 
 in which 
 R 9  represents hydrogen, (C 1 -C 6 )-alkyl or (C 3 -C 7 )-cycloalkyl, 
 R 10  represents hydrogen or (C 1 -C 6 )-alkyl, 
 and 
 in which phenyl and 5- or 6-membered heteroaryl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, trifluoromethyl, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy and (C 1 -C 4 )-alkylsulphonyl, 
 
           R 8  represents hydrogen or (C 1 -C 4 )-alkyl, 
           in which (C 1 -C 4 )-alkyl may be substituted by hydroxy, 
           or 
           R 7  and R 8  together with the carbon atom to which they are bonded form a 3- to 7-membered carbocycle or a 4- to 7-membered heterocycle, in which the 3- to 7-membered carbocycle and the 4- to 7-membered heterocycle may in turn be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine and (C 1 -C 4 )-alkyl, 
           L 3  represents a bond or (C 1 -C 4 )-alkanediyl,
 in which (C 1 -C 4 )-alkanediyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl, hydroxy and (C 1 -C 4 )-alkoxy, 
 
           n represents 0, 1 or 2, 
           the ring Q represents 3- to 7-membered carbocyclyl, 4- to 7-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, 
           where the ring Q may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, (C 1 -C 4 )-alkyl, trifluoromethyl, amino, hydroxy and (C 1 -C 4 )-alkoxy, 
         
         R 4  represents hydrogen, 
         R 5  represents hydrogen, halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl, (C 2 -C 4 )-alkenyl, (C 2 -C 4 )-alkynyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 4 )-alkoxy, amino, 4- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl, 
         R 6  represents hydrogen, cyano or halogen, 
         and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof. 
       
     
     
       2. Compound of  claim 1  in which
 A represents CH 2  or CH(CH 3 ), 
 R 1  represents (C 4 -C 6 )-alkyl, (C 4 -C 6 )-cycloalkyl, pyridyl or phenyl,
 where (C 4 -C 6 )-alkyl may be up to hexasubstituted by fluorine, 
 where (C 4 -C 6 )-cycloalkyl may be substituted by 1 to 4 fluorine substituents, and 
 where phenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, trifluoromethyl, methyl, cyclopropyl, methoxy and ethoxy, 
 where pyridyl may be substituted by 1 or 2 substituents, 
 
 R 2  represents hydrogen, (C 1 -C 4 )-alkyl, cyclopropyl or trifluoromethyl, 
 R 3  represents a group of the formula 
 
       
         
           
           
               
               
           
         
         
           where 
           * represents the point of attachment to the carbonyl group, 
           L 1  represents a bond or (C 1 -C 4 )-alkanediyl,
 in which (C 1 -C 4 )-alkanediyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, methyl and ethyl, 
 
           L 2  represents a bond, methylene, ethylene or propylene, 
           R 7  represents hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 5 )-cycloalkyl, —(C═O)—NR 9 R 10 , amino or phenyl,
 in which (C 1 -C 6 )-alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, hydroxy, methoxy, ethoxy, amino and phenyl,
 in which phenyl may be substituted by 1 to 3 fluorine substituents, in which (C 3 -C 5 )-cycloalkyl may be substituted by 1 or 2 fluorine substituents, 
 
 in which 
 R 9  represents hydrogen, (C 1 -C 4 )-alkyl, cyclopropyl or cyclobutyl, 
 R 10  represents hydrogen or (C 1 -C 4 )-alkyl, 
 and 
 in which phenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, trifluoromethyl, methyl, ethyl, methoxy and ethoxy, 
 
           R 8  represents hydrogen or (C 1 -C 4 )-alkyl, 
           or 
           R 7  and R 8  together with the carbon atom to which they are bonded form a 3- to 6-membered carbocycle,
 in which the 3- to 6-membered carbocycle may be substituted by 1 or 2 fluorine substituents, 
 
           L 3  represents a bond, methylene or ethylene,
 in which methylene and ethylene may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, methyl, ethyl and trifluoromethyl, 
 
           n represents 0 or 1, 
           the ring Q represents cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, phenyl, pyrazolyl, pyridyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl or triazolyl, 
           in which the ring Q may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy and ethoxy, 
         
         R 4  represents hydrogen, 
         R 5  represents hydrogen, fluorine, bromine, chlorine, cyano, methyl, ethyl, cyclopropyl, ethynyl, methoxy or ethoxy, 
         R 6  represents hydrogen or fluorine, 
         and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof. 
       
     
     
       3. Compound of  claim 1  in which
 A represents CH 2 , 
 R 1  represents 3-methylbutyl,
 where 3-methylbutyl may be up to hexasubstituted by fluorine, 
 or 
 represents cyclohexyl, 
 where cyclohexyl may be substituted by 2 fluorine substituents, 
 or 
 represents a phenyl group of the formula 
 
 
       
         
           
           
               
               
           
         
         
           where 
           # represents the point of attachment to A, 
           and 
           R 11  represents hydrogen or fluorine, 
           R 12  and R 13  represent fluorine, 
           or 
           represents a pyridyl group of the formula 
         
       
       
         
           
           
               
               
           
         
         
           where 
           # represents the point of attachment to A, 
         
         R 2  represents methyl, 
         R 3  represents a group of the formula 
       
       
         
           
           
               
               
           
         
         
           where 
           * represents the point of attachment to the carbonyl group, 
           L 1  represents a bond, methylene or ethylene, 
           L 2  represents a bond, methylene, ethylene or propylene, 
           R 7  represents hydrogen, methyl, ethyl, propyl, cyclopropyl, —(C═O)—NR 9 R 10 , amino or phenyl,
 in which methyl, ethyl and propyl may be substituted by hydroxy, methoxy, ethoxy or amino, 
 in which cyclopropyl may be substituted by 1 or 2 fluorine substituents, 
 in which 
 R 9  represents hydrogen, 
 R 10  represents hydrogen, 
 and 
 in which phenyl may be substituted by chlorine, 
 
           R 8  represents hydrogen or methyl, 
           or 
           R 7  and R 8  together with the carbon atom to which they are attached form a cyclopropyl ring or a cyclobutyl ring, 
           L 3  represents a bond or methylene, 
           n represents 0 or 1, 
           the ring Q represents cyclohexyl, piperidinyl, phenyl or pyrazolyl, 
           in which the ring Q may be substituted by methoxy or ethoxy, 
         
         R 4  represents hydrogen, 
         R 5  represents hydrogen, chlorine, methyl, cyclopropyl or methoxy, 
         R 6  represents hydrogen, 
         and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof. 
       
     
     
       4. Compound of  claim 1  in which
 A represents CH 2 , 
 R 1  represents a phenyl group of the formula 
 
       
         
           
           
               
               
           
         
         
           where 
           # represents the point of attachment to A, 
           and 
           R 11  represents hydrogen, 
           R 12  and R 13  represent fluorine, 
         
         R 2  represents methyl, 
         R 3  represents a group of the formula 
       
       
         
           
           
               
               
           
         
         
           where 
           * represents the point of attachment to the carbonyl group, 
           L 1  represents a bond, methylene or ethylene, 
           L 2  represents a bond, methylene or ethylene, 
           R 7  represents hydrogen, methyl, ethyl, cyclopropyl, —(C═O)—NR 9 R 10 , amino or phenyl,
 in which methyl and ethyl may be substituted by hydroxy, methoxy, ethoxy or amino, 
 in which 
 R 9  represents hydrogen, 
 R 10  represents hydrogen, 
 and 
 in which phenyl may be substituted by chlorine, 
 
           R 8  represents hydrogen or methyl, 
           or 
           R 7  and R 8  together with the carbon atom to which they are attached form a cyclopropyl ring or a cyclobutyl ring, 
           L 3  represents a bond or methylene, 
           n represents 0 or 1, 
           the ring Q represents cyclohexyl, piperidin-3-yl, phenyl or 1H-pyrazol-5-yl, in which phenyl may be substituted by methoxy or ethoxy, 
         
         R 4  represents hydrogen, 
         R 5  represents hydrogen, chlorine, methyl or methoxy, 
         R 6  represents hydrogen, 
         and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof. 
       
     
     
       5. Process for preparing the compound of  claim 1 , wherein
 [A] a compound of the formula (II) 
 
       
         
           
           
               
               
           
         
         in which A, R 1 , R 2 , R 4 , R 5  and R 6  are each as defined above and 
         T 1  represents (C 1 -C 4 )-alkyl or benzyl, 
         is reacted in an inert solvent in the presence of a suitable base or acid to give a carboxylic acid of the formula (III) 
       
       
         
           
           
               
               
           
         
         in which A, R 1 , R 2 , R 4 , R 5  and R 6  each have the meanings given above, 
         and this is subsequently reacted in an inert solvent under amide coupling conditions with an amine of the formula (IV-A) or (IV-B) 
       
       
         
           
           
               
               
           
         
         in which n, L 1 , L 2 , L 3 , Q, R 7  and R 8  each have the meanings given above, 
         or 
         [B] a compound of the formula (III-B) 
       
       
         
           
           
               
               
           
         
         in which R 2 , R 4 , R 5  and R 6  each have the meanings given above, 
         is reacted in an inert solvent under amide coupling conditions with an amine of the formula (IV) to give a compound of the formula (I-A) and (I-B) 
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         in which R 2 , R 4 , R 5 , R 6 , n, L 1 , L 2 , L 3 , Q, R 7  and R 8  each have the meanings given above, and the benzyl group is subsequently detached therefrom by the methods known to the person skilled in the art and the resulting compound of the formula (V-A) or (V-B) 
       
       
         
           
           
               
               
           
         
         in which R 2 , R 4 , R 5 , R 6 , n, L 1 , L 2 , L 3 , Q, R 7  and R 8  each have the meanings given above, is reacted in an inert solvent in the presence of a suitable base with a compound of the formula (VI) 
       
       
         
           
           
               
               
           
         
         in which A and R 1  have the meaning given above and 
         X 1  represents a suitable leaving group, in particular chlorine, bromine, iodine, mesylate, triflate or tosylate, 
         pthen any protective groups present are detached, and the resulting compounds of the formula (I) are optionally converted with the appropriate (i) solvents and/or (ii) acids or bases to the solvates, salts and/or solvates of the salts thereof. 
       
     
     
       6. Medicament comprising the compound of  claim 1  in combination with an inert, non-toxic, pharmaceutically suitable excipient. 
     
     
       7. Medicament comprising the compound of  claim 1  in combination with a further active compound selected from the group consisting of organic nitrates, NO donors, cGMP-PDE inhibitors, antithrombotic agents, hypotensive agents and lipid metabolism modifiers.